Process for anion exchange of thiamin salts



Patented May 20, 1952 x UNITED STATES PATENT OFFICE PROCESS FOR ANION EXCHANGE OF THIAMIN SALTS Eugene E. Howe. Bound Brook, and Max Tishler, Westfield, N. J., assignors to Merck & 00., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application August 6, 1947, Serial No. 766,890

11 Claims. (01. zen-256.6)

l 2 This invention is concerned, generally, with ploy resins of the phenol-formaldehyde type the preparation of salts of vitamin B1; more parwhich are chemically or structurally characterticularly, it relates to the inter-conversion of ized by the presence of aminoalkylene aminothiamin salts utilizing anion-exchange synthetic methyl substituents on the phenyl nuclei. (A resins. commercially available resin of this type, which Vitamin B1 is usually synthesized by processes can be prepared as described in Example 4 of which result in the initial production of thia- U. S. Patent 2,402,384, which'issued on June 18, min bromide hydrobromide. This salt is ordinar- 1946, is sold by the Resinous Products and Chemily converted to another vitamin B1 salt, suitable ical Company under the trade name of Amberlite for therapeutic use, such as thiamin chloride hy- IR-4b.)

drochloride or thiamin nitrate. This inter-con- The resin-anion component may be prepared by version of thiamin salts has been accomplished passing a solution containing the desired anion previously by reacting thiamin bromide hydrothrough a bed of the resin in a column. and then bromide with the appropriate silver salt, but the Washing the resin with Water to remove unreproducts thus obtained are usually contaminated acted solution from the column. The reaction with silver and require further purification. between the resin and anion is best carried out Moreover; large amounts of silver are employed using the corresponding acid, as for example, hyin such procedures, and the recovery of this sildrochloric acid. This procedure avoids the introver, and the unavoidable losses of silver which n duction of undesired cations. Moreover, the i ioccur, add considerably to the manufacturing cost tial useof an acid is necessary in the case of cerof vitamin B1. tain hydroxyl, and carbonate resins, since these We have now discovered, that a, salt of vit mi resins are often non-reactive with neutral solu- Bi with any desired anion is readily prepared in tions, such as sodium chloride. However, it is high yield and in substantially pure form from Often desired p p reSin-eXehengeIs any other vitamin B1 salt. This is accomplished taming anions of weak acids, such as acetate ion, by reacting a solution of said vitamin B1 salt with 0 containing anions f oxidizing acids to w i h an anion-exchange synthetic resin containing the h r in i bl s h s ni r te anion- The desired anion. We ordinarily prefer to conduct preparation of such resin-exchangers is ordithe reaction between the vitamin B: salt and the herily accomplished by first preparing the resinaifion-exchange resin by passin the sohiti n of 3?) chloride, and then reacting said resin-chloride vitamin B1 salt through a column containing the h a Solution Containing a salt of he desired resin-anion component. This method avoids the anion, sodium nitrate, sodium acetate, and use of expensive silver salts, thus avoiding silthe l y this p c the nitrate r s ever contamination of the product, and results in v, s i011, p es the Chloride anion o pr uc the direct production of substantially pure the corresponding resin-nitrate or resin acetate, product in high yield. A further advantage of respectively, and the chloride ion is transferred to this process is that contaminating anions, such the effluent in lihe form sodium h or as sulfate, and heavy metal cations, such as lead, After the resin-anion Component has been p copper, nickel, and iron, which form complexes pared, an aqueous solution of the vitamin Bl salt with the resin employed, are lik i removed 40 which is to be converted is passed th ou h the A special feature of thi process i th t concencolumn containing said resin at a suitable rate trated vitamin B1 salt solutions can be converted achieve s Complete eenversien as p s It without appreciable losses due to vitamin adis p l to operate the column using solutions sorption by the resin. containing extremely low concentration of vita- Althou h ou m and improved process is min B1. It is ordinarily preferred, however, to generally applicable fo the in er-conversion of employ aqueous solutions in which the concenvitamin B1 salts, it is ordinarily employed for trat on of vitamin B1 salt is about 20-25%- treating hydrohalic acid salts of vitamin B1 and, The eeilieeity 0f the resin for Converting tain particular, for preparing thiamin chloride hymin Bi salt such as thiamin bromide hy drochloride, the nitric acid salt of thiamin nirate, bromide, Wit out a y break-through 0f iShe b the acetic acid salt of thiamin acetate, and the mide ion, is t determined eXpelimenteilly, like, from thiamn bromide hydrobromide. e. g. in the case of the Amberlite IR-4b resin Resinous materials containing basic groups, described above, the total capacity of the resinsuch as amino groups, are employed as the anionchloride obtained from gms. of dried resin exchange resin. It is ordinarily preferred to em- 5 is about 87 gms. of thiamin bromide hydrobromide. Employing a in. column containing resin-chloride prepared from 100 gms. of dried resin, the break-through of bromide ion, occurs after about 75 gms. of thiamin bromide hydrobromide has been converted. By regulating the amount of vitamin B1 salt passed through the column, it is possible to completely convert said vitamin B1 salt at a single pass, the holdback in the column being recovered by washing the column with distilled water. B1 salt thus produced is recovered from the aqueous effluent by conventional means, as, for example, by concentrating the solution and precipitating said vitamin B1 salt by the addition of alcohols, such as isopropanol.

In technical operation, however, it is preferred to take as large a first cut of converted vitamin 3] salt solution, free of starting anions, as possible, and the vitamin B1 salt is recovered from this aqueous solution as previously described. The column is then washed with water, and the resulting efiiuent, which contains a mixture of starting and final salts of vitamin B1, is utilized as starting solution for the next run of the column. The resin column, which, at this point, is substantially saturated with the starting anion, is again treated with a solution of the desired anion as described above. The resin column is washed with water as in the first cycle to remove unreacted solution from the column. 1

The column is then ready for converting additional vitamin B1 salt.

The following examples illustrate methods of carrying out the present invention, but it is to be. understood that these examples. are given by way of illustration and not QflimitatiQn.

Example 1:

Ten grams of Amberlite IR- ib (an anion exchange resin manufactured by the Resinous Products and Chemical Company, and which is prepared as described above), was treated in a beaker with 100 cc. of 10% hydrochloric acid. When evolution of carbon dioxide had almost ceased, the hydrochloric acid was removed by decantation and the resin was placed in a 10 mm. glass tube forming a column 10 inches in height. 100 cc. of 5% hydrochloric acid was then passed through the column at the rate of 2 cc. per minute and this was followed by about 50 cc. of distilled water until the efiiuent gave only a slight test for chloride.

A solution of 6.0 gms. of thiamin bromide hydrobromide in cc. of water was passed through the column of resin, prepared as described above, at the rate of 0.5 cc. per minute. This solution was followed by cc. of water at the same rate. The combined effluent and wash was decolorized by treatment with 0.2 gms. of activated charcoal and evaporated to a volume of 12 cc. 145 cc. of isopropanol was added to the result ing solution, after which the aqueous-isopropanol mixture was cooled to 5 C. and held at that temperature overnight. The precipitated thiamin chloride hydrochloride was recovered by filtering, washed with 25 cc. of isopropanol and dried to constant weight at 60 0., to produce 4.0 gms. of substantially pure material. The mother liquor was reconcentrated and a second crop of 0.2 gms. was obtained therefrom, which resulted in an overall yield of 4.2 gms., 88.7% of theory; M. P. 237-238 C. A fluorescein spot test indicated less than 0.1% contamination with thiamin bromide hydrobromide.

The vitamin Example 2 5.0 gms. of vitamin B1 hydrochloride was dissolved in 25 cc. of water and passed through a column of resin which had previously been used for the conversion of the hydrobromide to the hydrochloride; (the resin column em-- ployed thus contained resin-bromide). The effluent was found to contain no ionic chloride indicating a complete reversal of the exchange reaction carried out in Example 1.

Example 3 The procedure described in Example 1 was followed, except that soluble salts (nitrates) of copper, lead, nickel and iron were added to the vitamin B1 hydrobromide solution. The metals were present in the following concentrations: copper-600 p. p. m. (parts per million), lead 800 p. p. nickel-500 p. p. m., and iron- 400 p. p. m. The copper, lead, and nickel content of the isolated thiamin chloride hydrochloride was approximately 75 p. p. m., while the iron content was less than 20 p. p. m.

Example 4 About 12 gms. of Amberlite IR- lo was treated with aqueous hydrochloric acid substantially as described in Example 1 to produce a column of resin-chloride substantially 12 inches in height in a glass tube approximately 10 mm. in diameter. About cc. of aqueous 5% sodium nitrate solution was then passed through the column at a rate of approximately 2 cc. per minute, followed by approximately 5.0 cc. of, water. (A nitrate saltymust housed. fonthe preparation of the column. since Amberlite 13-411 is unstable to nitric acid. Moreover, the resin must first be reacted with an acid. since thephydroxyl and carbonate groupings of the resinare non-reactive with neutral sodium nitrate.)

A 20% aqueous solution of thiamin bromide hydrobromide was passed through the column, prepared as described above, at a rate. of ap proximately 05 cc. per minute. The breakthrough of bromide ion occurred after the passage of solution containing approximately 50 gms. of thiamin bromide hydrobromide per 100 gms. of dried resin. The total capacity of the resin was found to be approximately gms. of thiamin bromide hydrobromide per 100 gms. of dried resin.

Example 5 A 20% solution of thiamin bromide hydrobromide was passed through a column, packed to a depth of approximately 20 inches with resinnitrate prepared as described in Example 4 from about 26 gms. of dried Amberlite IR- lb. The rate of flow was again 0.5 cc. per minute, so that the contact time was approximately doubled. The efiiuent solution, collected before the breakthrough of bromide ion, was titrated with N/lO sodium hydroxide solution using phenolphthalein as an indicator. This titration indicates that resin-nitrate prepared from 100 gms. of dried resin converts about 52 gms. of thiamin bromide hydrobromide to the nitrate before the breakthrough of bromide ion.

Example 6 About 10 gms. of dried Amberlite IR-lb (as shipped) was placed in a 10 mm. glass column, thus forming a resin column approximately 10 inches in height. Approximately 100 cc. of 5% aqueous hydrochloric acid was passed through this column at a rate of approximately 2 cc. per

minute, followed by approximately 200 cc. of 5% aqueous sodium acetate solution, also at a rate of approximately 2 cc. per minute, and the column was then washed with about 50 cc. of distilled water. A 5% aqueous solution of thiamin bromide hydrobromide was then passed through the column at a rate of approximately 0.5 cc. per minute; the break-through of bromide ion occurred after approximately 7.50 gms.. oi thiamin bromide hydrobromide had been converted. After approximately 12.5 gms. of vitamin had been fed into the column, the bromide ion concentrations of the original and efiiuent solution were substantially equal. A total of 10.0 gms. of the hydrobromide was converted to the acetic acid salt of thiamin acetate. The pH of v the original solution was 4.1 and that of the eiiiuent prior to the break-through of bromide. ion was approximately 5.4. The acetic acid salt of thiamin monoacetate may be recovered from this eflluent by conventional means. Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims.

We claim:

1. The process of preparing a salt of vitamin B1 which comprises reacting an aqueous solution containing another salt of vitamin B1 with a polyamine-formaldehyde anion-exchange synthetic resin, said resin containing the same anion as the salt which it is desired to produce, whereby an anion exchange takes place between said salt of vitamin B1 and the anion of the synthetic resin to produce the desired salt of vitamin B1, separating the aqueous solution containing said vitamin B1 salt fromsaid resin, and recovering said vitamin B1 salt from said solution.

2. The process of preparing a salt of vitamin B1 which comprises reacting an aqueous solution containing a hydrohalic acid salt of vitamin B1 with a polyamine-formaldehyde anion-exchange synthetic resin, said resin containing the same anion as the salt which it is desired to produce, whereby an anion exchange takes place between said hydrohalic acid salt of vitamin B1 and the anion of the synthetic resin to produce the desired salt of vitamin B1, separating the aqueous solution containing said vitamin B1 salt from said resin, and recovering said vitamin B1 salt from said solution.

3. The process of preparing an aqueous solution containing a salt of vitamin B1 substantially free of contaminating anions, and cations of heavy metals, from an aqueous solution containing another salt of vitamin B1 together with said ionic impurities, which comprises reacting said aqueous solution with a polyamine-formaldehyde anion-exchange synthetic resin, said resin containing the same anion as the salt which it is desired to produce, thereby producing the desired salt of vitamin B1 and at the same time removing said contaminating ions, and separating the aqueous solution containing said vitamin B1 salt from said resin.

4. The process of preparing thiamin chloride hydrochloride which comprises reacting an aqueous solution containing thiamin bromide hydrobromide with a polyamine-formaldehyde anion-exchange synthetic resin containing chloride anion, whereby an anion exchange takes place between said thiamin bromide hydrobromide and the resin-chloride to produce thiamin chloride hydrochloride, separating the aqueous solution containing said thiamin chloride hydrochloride from said resin, and recovering said thiamin chloride hydrochloride from said solution.

5. The process of preparing the nitric acid salt of thiamin nitrate which comprises reacting an ing said nitric acid salt of thiamin nitrate fromsaid solution.

6. The process of preparing the acetic acid salt of thiamin acetate which comprises reacting an aqueous solution containing thiamin bromide hydrobromide with polyamine-formaldehyde anionexchange synthetic resin containing acetate anion, whereby an anion-exchange takes place between said thiamin bromide hydrobromide and the resin-acetate to produce the acetic acid salt of thiamin acetate, separating the aqueous solution containing said acetic acid salt of thiamin acetate from said resin, and recovering said acetic acid salt of thiamin acetate from said solution.

7. The process of preparing a salt of vitamin B1 which comprises passing an aqueous solution, said solution having a pH of about 0.5 and containing another salt of vitamin B1 in a concentratlon of about 20% through a column containing a polyamine-formaldehyde anion-exchange synthetic resin, said resin containing the same anion as the salt which it is desired to produce, whereby an anion exchange takes place between said salt or vitamin B1 and the anion of the synthetic resin to produce an aqueous effluent containing the desired salt of vitamin B1 in a concentration of about 20%, and recovering said vitamin B1 salt from said aqueous effluent.

8. The process of preparing thiamin chloride hydrochloridewhich comprises passing an aqueous solution having a thiamin bromide hydrobromide concentration of about 20% and a pH of about 0.5 through a column packed with a polyamine formaldehyde anion-exchange synthetic resin containing chloride anion, whereby an anion-exchange takes place between said thiamin bromide hydrobromide and the chloride anionof the synthetic resin to produce an aqueous efliuent having a thiamin chloride hydrochloride concentration of approximately 20%, and substantially free of thiamin bromide hydrobromide, and recovering substantially pure thiamin chloride hydrochloride from said efiluent; passing wash water through said column thereby separating the residual vitamin B1 salts from said resin as an aqueous wash solution, then passing through the column a solution containing, chloride anion followed by wash water thereby forming the resin-chloride component, substantially free of contaminating ions, finally passing said aqueous wash solution containing residual vitamin B1 salts through the resin chloride, thereby converting residual thiamin bromide hydrobromide in said wash solution to thiamin chloride hydrochloride, and recovering said thiamin chloride hydrochloride from the aqueous effluent thus produced, and repeating the foregoing cycle.

9. The process of preparing the nitric acid salt of thiamin nitrate which comprises passing an aqueous solution having a thiamin bromide hydrobromide concentration of about i 20 7a and a pH o'fabo'ut 0.5 througha' column packed with a polyamine formaldehyde anion-exchange: sym thetic resin" containing nitrate anion, whereby an anion exchange takes place between said thiamin" bromide hydrobromide and the nitrate anion of the synthetic resin'to produce an aqueous efiluent having aconcentration of the nitric acid salt of thiamin nitrate of approximately 20%, and substantially free of thiamin bromide hydrobromide, and recovering substantially pure nitric acid salt of thiamin nitrate from said eiiiuent; passing wash water'through said column thereby separating the residualvitamin Br salts from said resinas an aqueous Wash solution, then passing through the column a solution containing nitrate anion followed by wash water thereby forming" the resin-nitrate component, substantially free of contaminating. ions, finally passing said aqueous wash solution containing residual vitamin B1 salts through the resin-nitrate, thereby converting residual thiamin bromide hydrobromide in-said wash solution-to the nitric acid salt of thiamin nitrate and recovering said nitric acid salt of thiamin nitrate from the aqueous effluent thus produced, and repeating the foregoing cycle.

10. The process of preparing the acetic acid salt of thiamin acetate which comprises passingan aqueous solution having a thiamin bromide hydrobromide concentration of about 20% and a pH-of about 0.5 through a column packed with a polyamine formaldehyde anion-exchange synthetic resin containing acetate anion, whereby an anion exchange takes plac'ebetween said thiamin bromide hydrobromide and the acetate anion of the synthetic resin to produce an aqueous efliuent havinga concentration of the acetic acid salt of thiamin acetate of approximately 20%, andsubstantially free of thiamin bromide hydrobromide, and recove'ring substantially pure acetic acid salt of thiamin acetate from said efiiue'nt; passing wash water through said column thereby separating the residual vitamin B1 salts from said resin as an aqueous through'the column a solution containing acetate anion followed by wash water thereby forming the resin-acetate component, substantially free of contaminating ions, finally passing'said aqueouswash solution containing residual vitamin Bi salts through the resin-acetate thereby converting residual thiamin bromide hydrobromide in said wash solution to the acetic acid salt of thiamin acetate, and recovering said acetic acid wash solution, then passing 8. saltof thiamin acetate from the aqueous'efiiuent thus produced; and repeating. the foregoing. cycle.

11. The process of preparing thiamin chloride hydrochloridewhich comprises passingv a solution containing chloride ion followed by wash: water through acolumn packed with a polyamineformaldehyde anion-exchange synthetic resin thereby converting. the'resin to the chloride cycle, passing an aqueous solution having a thiamin bromide hydrobromide concentration of about 20% and a pH of about 0.5 through said resin column thereby effecting an anion exchange between the thiamin bromide hydrobromide and the resin-chloride to produce an aqueous efiiuent containing approximately 20% thiamin chloride hydrochloride, passing wash water through the column thereby separating said efiluent from said resin, recovering thiamin chloride hydrochloride from said effluent, then passing through the column a solution containing chloride ion followed by wash water thereby reconverting. the

resin to the chloride cycle substantially uncontaminated with organic and inorganic impurities, and repeatedly carrying out the foregoing. anionexchange and regeneration operations.

EUGENE E. HOWE. MAX TISHLER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Appelzweig:- J. Am. Chem. Soc., 66, 1990 (1944). Applezweig et al.: Ind. and Eng. Chem., 38, pp.

Myers: Ind. and Eng. Chem., 35, No. 8, 858-863 Englis et al.: Ind. and Eng. Chem., 36, 609 (1944).

Sussman et al.: 618-624 (1945).

Ind. and Eng. Chem. 37, 

1. THE PROCESS OF PREPARING A SALT OF VITAMIN B1 WHICH COMPRISES REACTING AN AQUEOUS SOLUTION CONTAINING ANOTHER SALT OF VITAMIN B1 WITH A POLYAMINE-FORMALDEHYDE ANION-EXCHANGE SYNTHETIC RESIN, SAID RESIN CONTAINING THE SAME ANION AS THE SALT WHICH IT IS DESIRED TO PRODUCE, WHEREBY AN ANION EXCHANGE TAKES PLACE BETWEEN SAID SALT OF VITAMIN B1 AND THE ANION OF THE SYNTHETIC RESIN TO PRODUCE THE DESIRED SALT OF VITAMIN B1, SEPARATING THE AQUEOUS SOLUTION CONTAINING SAID VITAMIN B1 SALT FROM SAID RESIN, AND RECOVERING SAID VITAMIN B1 SALT FROM SAID SOLUTION. 